Heterocyclic derivatives

Abstract

The invention relates to heterocyclic derivatives of formula (I) A—B—X 1 —T 1 (R 2 )—L 1 —T 2 (R 3 )—X 2 —Q  (I) or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.

1. A compound of formula (I)
   A—B—X 1 —T 1 (R 2 )—L 1 —T 2 (R 3 )—X 2 —Q  (I) 
 
 
       wherein:
 A is 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms selected form nitrogen, optionally substituted by one, two or three atoms or groups selected from halo, oxo, carboxy, trifluoromethyl cyano, amino, hydroxy, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkylamino or di-C 1-4 alkylamino;  
 B is a phenylene ring optionally substituted by one or two substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, from the substituent —(CH 2 ) n Y 1  wherein n is 0-4 and Y 1  is selected from hydroxy, amino, carboxy, C 1-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, C 1-4 alkylamino, di-C 1-4 alkylamino, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazin-1-yl, 4-C 1-4 alkylpiperazin-1-yl, C 1-4 alkylthio, C 1-4 -alkylsulphinyl, C 1-4 alkylsulphonyl, C 2-4 alkanoylamino, benzamido, C 1-4 alkylsulphonamido and phenylsulphonamido, from the substituent —(CH 2 ) n Y 2  wherein n is 0-4 and Y 2  is selected from carboxy, carbamoyl, C 1-4 alkoxycarbonyl,  N —C 1-4 alkylcarbamoyl,  N , N -di-C 1-4 -alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 1-oxothiomorpholinocarbonyl, 1,1-dioxothiomorpholinocarbonyl, piperazin-1-ylcarbonyl, 4-C 1-4 alkylpiperazin-1-ylcarbonyl, C 1-4 alkylsulphonamidocarbonyl, phenylsulphonamidocarbonyl and benzylsulphonamidocarbonyl, from a substituent of the formula —X 3 —L 2 —Y 2  wherein X 3  is a group of the formula CON(R 5 ), CON(L 2 —Y 2 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 2 —Y 2 ), L 2  is C 1-4 alkylene, Y 2  has any of the meanings defined immediately hereinbefore and each R 5  is independently hydrogen or C 1-4 alkyl, and  
 from a substituent of the formula —X 3 —L 3 —Y 1  wherein X 3  is a group of the formula CON(R 5 ), CON(L 3 —Y 1 ), C(R 5 ) 2 O, O, N(R 5 ) or N(L 3 —Y 1 ), L 3  is C 2-4 alkylene, Y 1  has any of the meanings defined immediately hereinbefore and each R 5  is independently hydrogen or C 1-4 alkyl,  
 and wherein any heterocyclic group in a substituent of B optionally bears 1 or 2 substituents selected from carboxy, carbamoyl, C 1-4 alkyl, C 1-4 alkoxycarbonyl,  N —C 1-4 alkylcarbamoyl and  N,   N -di-C 1-4 alkylcarbamoyl,  
 and wherein any phenyl group in a substituent of B optionally bears 1 or 2 substituents selected from halo, trifluoromethyl, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-4 alkenyloxy and C 2-4 alkynyloxy;  
 T 1  and T 2  are N, L 1  is ethylene, and R 2  and R 3  are joined to form an ethylene such that R 2  and R 3 , together with T 1  and T 2  and L 1 , form a piperazine ring;  
  wherein the heterocyclic ring formed by T 1 , T 2 , L 1 , R 2  and R 3  is optionally substituted by one or two substituents selected from hydroxy, oxo, carboxy and C 1-4 alkoxycarbonyl; or one of the following: 
 —(CH 2 ) n —R, —(CH 2 ) n —NRR 1 , —CO—R, —CO—NRR 1 , —(CH 2 ) n —CO—R and —(CH 2 ) n —CO—NRR 1 ;  
 wherein n is 0, 1 or 2, preferably n is 1 or 2;  
 R and R 1  are independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyC 1-4 alkyl, carboxyC 1-4 alkyl and C 1-4 alkoxycarbonylC 1-4 alkyl or where possible R and R 1  may together form a 5- or 6-membered optionally substituted saturated or partially unsaturated heterocyclic ring which may include in addition to the nitrogen to which R and R 1  are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulphur;  
 
 X 1  is SO, SO 2 , C(R 4 ) 2  or CO, wherein each R 4  is independently hydrogen or C 1-4 alkyl;  
 X 2  is S(O) y  wherein y is one or two, C(R 5 ) 2  or CO; and each R 5  is hydrogen or C 1-4 alkyl;  
 Q is phenyl, naphthyl, phenylC 1-4 alkyl, phenylC 2-4 alkenyl, phenylC 2-4 alkynyl or a heterocyclic moiety containing up to 4 heteroatoms selected from nitrogen, oxygen and sulphur 
 and Q is optionally substituted by one, two or three substituents selected from halo, trifluromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, trifluoromethylsulphonyl, carboxy, carbamoyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 -alkoxycarbonyl,  N —C 1-4 alkylcarbamoyl,  N,   N -di-C 1-4 alkylcarbamoyl, C 2-4 alkanoyl, C 2-4 -alkanoylamino, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, carboxyC 1-4 alkyl, C 1-4 -alkoxycarbonylC 1-4 alkyl, carbamoylC 1-4 alkyl,  N —C 1-4 alkylcarbamoylC 1-4 alkyl,  N,   N -di-C 1-4 -alkylcarbamoylC 1-4 alkyl, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl, benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl,  
 and wherein said heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent is a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from nitrogen, oxygen and sulphur,  
 and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1, 2 or 3 substituents selected from halo, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxycarbonyl,  N —C 1-4 alkylcarbamoyl,  N ,  N -di-C 1-4 alkylcarbamoyl and C 2-4 alkanoylamino;  
 
 
       or a pharmaceutically acceptable salts thereof. 
     
     
       2. A compound of formula (I) according to  claim 1  wherein A is a pyridyl, pyrimidinyl or pyridazinyl ring. 
     
     
       3. A compound of formula (I) according to  claim 2  wherein A is 4-pyrimidinyl or 4-pyridyl. 
     
     
       4. A compound of formula (I) according to  claim 1  wherein B is paraphenylene. 
     
     
       5. A compound of formula (I) according to  claim 1  wherein the ring formed by T 1 , R 2 , R 3 , T 2  and L is 1,4-piperazinediyl. 
     
     
       6. A compound of formula (I) according to  claim 1  wherein X 1  is CO. 
     
     
       7. A compound of formula (I) according to  claim 1  wherein X 2  is SO 2 . 
     
     
       8. A compound of formula (I), according to  claim 1 , wherein
 A is pyridyl, pyrimidinyl, or pyridazinyl;  
 B is para-phenylene;  
 X 1  is CO, SO 2  or CH 2 ;  
 —T 1 (R 2 )—L 1 —T 2 (R 3 )—forms a piperazine ring;  
 X 2  is SO 2 ;  
 Q is styryl or naphthyl optionally substituted by fluoro, chloro or bromo or is phenyl optionally substituted by fluorophenyl, chlorophenyl, or bromophenyl;  
 
       or a pharmaceutically-acceptable salts thereof. 
     
     
       9. A pharmaceutical formulation comprising a compound of formula (I) according to any one of  claims 1  to  8  and a pharmaceutically-acceptable diluent or carrier. 
     
     
       10. A method of preventing or treating a Factor Xa mediated disease or medical condition comprising administering to a patient a pharmaceutically effective amount of a compound of formula (I), as defined in any one of  claims 1  to  8 . 
     
     
       11. A process for preparing a compound of formula (I), are defined in  claim 1 ,comprising:
 (a) for the production of those compounds of the formula (I) wherein T 1  is N and X 1  is CO, the reaction, conveniently in the presence of a suitable base, of an amine of formula (II) 
   HN(R 2 )—L 1 —T 2 (R 3 )—X 2 —Q  (II) 
 
 
  with an acid of the formula (III) 
   A—B—COOH  (III) 
 
 
  or a reactive derivative thereof;  
 (c) for the production of those compounds of the formula (I) wherein T 1  is N and X 1  is CH(R 4 ), the reductive amination of a keto compound of the formula (VI): 
   A—B—CO—R 4   (VI) 
 
 
  wherein R 4  is hydrogen or C 1-4 alkyl, with an amine of the formula (II) as defined above;  
 (d) the reaction of a compound of the formula (VII): 
   Z—B—X 1 —T 1 (R 2 )—L 1 —T 2 (R 3 )—X 2 —Q  (VII) 
 
 
  wherein Z is a displaceable group with an activated derivative of ring A;  
 (e) by forming A ring on compounds of formula (VII), wherein Z is a functional group capable of cyclisation;  
 (f) for the production of compounds wherein T 2  is N, the reaction of a compound of the formula (VIII): 
   A—B—X 1 —T 1 (R 2 )—L 1 —NH(R 3 )  (VIII) 
 
 
  with a compound of the formula (IX): 
   Z—X 2 —Q  (IX) 
 
 
  wherein Z is a displaceable group;  
 (g) for the production of compounds wherein T 1  is N and X 1  is SO or SO 2 , the reaction of a compound of the formula (II) as defined above with a compound of the formula (X): 
   A—B—SO x—Z   (X) 
 
 
  wherein x is one or two and Z is a displaceable group;  
 (h) for production of compounds of formula (I) by coupling T 2  to Q and thus preparing the —T 2 —X 2 —Q moiety, methods analogous to those described in process variants (a), (c) and (g) for preparing the B—X 1 —T 1 — moiety may be employed;  
 (i) for the production of compounds of formula (I) wherein X 1  is a group of the formula SO, SO 2 , wherein B bears a C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, 1-oxothiomorpholino or 1,1-dioxothiomorpholino group, wherein X 2  is a group of the formula SO or SO 2 , wherein Q bears a C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, phenylsulphinyl, phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group, the oxidation of the corresponding compound of the formula (I) which contains X 1  as a thio group.